Background: Fatigue is a serious and potentially disabling symptom of Gulf War Illness (GWI). Current estimates from the Research Advisory Committee on Gulf War Illnesses are that 25% of all Gulf Veterans (GVs) have GWI with fatigue being a primary symptom. The importance of gaining a better understanding of fatigue is illustrated by the fact that a primary complaint of those reporting chronic fatigue is that their fatigue is worsened by the physical and cognitive demands of daily life resulting in a significant number of military personnel that are no longer able to perform their duties. It is precisely this fatigue that is exacerbated by mental and physicl demands of the day-cognitive fatigue-that has remained understudied and that is the focus of the current proposal. Objective: The overall objective of this study is to establish the network o brain areas underlying cognitive fatigue in persons with GWI. This will be done by looking at cognitive fatigue as a trait of GWI, and by looking at cognitive fatigue as a state that individual with GWI are more prone to than healthy Veteran controls. Aims of the current study 1) To establish fMRI as an objective measure of cognitive fatigue in GVs with GWI. 2) To examine the relationship between the objective measure of cognitive fatigue with valid self-report measures of fatigue. 3) To use Diffusion Tensor Imaging (DTI) methods to determine both whether white matter tract integrity differs between Veterans with GWI and healthy Veteran controls, and whether these differences are related to functional brain imaging and self-report fatigue outcomes. Study Design: The proposed study will induce cognitive fatigue with tasks that require sustained mental effort and examine the associated functional changes in the brain. This approach has proved critical in CFS, MS and TBI and we plan to extend this work to GWI, using a series of cognitive tasks to test our hypotheses. The first task will induce cognitive fatigue in GVs with GWI through sustained performance of an attention task, a modified version of the Paced Auditory Serial Addition Task (mPASAT), in the MRI scanner. This is a working memory task in which subjects are presented with a sequential series of digits and must decide whether or not the two most recently presented digits sum to 10. After each block of the fatiguing cognitive task, cognitive fatigue will be assessed using a Visual Analogue Scale of fatigue (VAS-F) to determine whether increases in brain activity over time in predefined brain regions hypothesized to underlie cognitive fatigue are correlated with increases in subjective cognitive fatigue. Second, the GVs will be given a non-fatiguing task that we have found does not discriminate between fatigued and healthy participants, further highlighting the importance of fatigue provocation in fatiguing illness. Third, in order to better understand the relationship between subjective fatigue, increases in cerebral brain activity and white matter integrity, we wil obtain diffusion weighted images of the brain. We hypothesize that there will be disruption of the white matter tracts that connect the key areas of the brain that are implicated in fatigue. Impact This proposal represents a first step towards establishing the set of brain regions that are criticl to fatigue. It is no exaggeration to say that this would represent a paradigm shift in research on fatigue. Once this set of areas is determined, the contribution of each individual area can be determined. Treatments can be devised that act on these areas, and the effectiveness of treatments can be assessed by reference to the activity in these regions. Aspects of this approach have been successfully applied to better understand both chronic pain and fatigue in civilian populations, and the comprehensive approach proposed here may help future researchers to further examine the mechanisms of fatigue in GWI.